title: The folliculin tumor suppressor is a GAP for the RagC/D GTPases that signal amino acid levels to mTORC1.
abstract: The mTORC1 kinase is a master growth regulator that senses numerous environmental cues, including amino acids. The Rag GTPases interact with mTORC1 and signal amino acid sufficiency by promoting the translocation of mTORC1 to the lysosomal surface, its site of activation. The Rags are unusual GTPases in that they function as obligate heterodimers, which consist of RagA or B bound to RagC or D. While the loading of RagA/B with GTP initiates amino acid signaling to mTORC1, the role of RagC/D is unknown. Here, we show that RagC/D is a key regulator of the interaction of mTORC1 with the Rag heterodimer and that, unexpectedly, RagC/D must be GDP bound for the interaction to occur. We identify FLCN and its binding partners, FNIP1/2, as Rag-interacting proteins with GAP activity for RagC/D, but not RagA/B. Thus, we reveal a role for RagC/D in mTORC1 activation and a molecular function for the FLCN tumor suppressor.
authors.affiliation: Whitehead Institute for Biomedical Research and Massachusetts Institute of Technology, Department of Biology, Nine Cambridge Center, Cambridge, MA 02142, USA.|Koch Institute for Integrative for Cancer Research, 77 Massachusetts Avenue, Cambridge, MA 02139, USA.
authors.forename: Zhi-Yang
authors.initials: ZY
authors.lastname: Tsun
authors.affiliation: Whitehead Institute for Biomedical Research and Massachusetts Institute of Technology, Department of Biology, Nine Cambridge Center, Cambridge, MA 02142, USA.|Koch Institute for Integrative for Cancer Research, 77 Massachusetts Avenue, Cambridge, MA 02139, USA.
authors.forename: Liron
authors.initials: L
authors.lastname: Bar-Peled
authors.affiliation: Whitehead Institute for Biomedical Research and Massachusetts Institute of Technology, Department of Biology, Nine Cambridge Center, Cambridge, MA 02142, USA.|Koch Institute for Integrative for Cancer Research, 77 Massachusetts Avenue, Cambridge, MA 02139, USA.
authors.forename: Lynne
authors.initials: L
authors.lastname: Chantranupong
authors.affiliation: Whitehead Institute for Biomedical Research and Massachusetts Institute of Technology, Department of Biology, Nine Cambridge Center, Cambridge, MA 02142, USA.|Koch Institute for Integrative for Cancer Research, 77 Massachusetts Avenue, Cambridge, MA 02139, USA.
authors.forename: Roberto
authors.initials: R
authors.lastname: Zoncu
authors.affiliation: Whitehead Institute for Biomedical Research and Massachusetts Institute of Technology, Department of Biology, Nine Cambridge Center, Cambridge, MA 02142, USA.|Koch Institute for Integrative for Cancer Research, 77 Massachusetts Avenue, Cambridge, MA 02139, USA.
authors.forename: Tim
authors.initials: T
authors.lastname: Wang
authors.affiliation: Whitehead Institute for Biomedical Research and Massachusetts Institute of Technology, Department of Biology, Nine Cambridge Center, Cambridge, MA 02142, USA.|Koch Institute for Integrative for Cancer Research, 77 Massachusetts Avenue, Cambridge, MA 02139, USA.
authors.forename: Choah
authors.initials: C
authors.lastname: Kim
authors.affiliation: Whitehead Institute for Biomedical Research and Massachusetts Institute of Technology, Department of Biology, Nine Cambridge Center, Cambridge, MA 02142, USA.
authors.forename: Eric
authors.initials: E
authors.lastname: Spooner
authors.affiliation: Whitehead Institute for Biomedical Research and Massachusetts Institute of Technology, Department of Biology, Nine Cambridge Center, Cambridge, MA 02142, USA.|Koch Institute for Integrative for Cancer Research, 77 Massachusetts Avenue, Cambridge, MA 02139, USA.|Howard Hughes Medical Institute, Department of Biology, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.
authors.forename: David M
authors.initials: DM
authors.lastname: Sabatini
mesh_terms: D000596:Amino Acids / Q000378:metabolism*; D002352:Carrier Proteins / Q000378:metabolism; D020690:GTPase-Activating Proteins / Q000502:physiology; D057809:HEK293 Cells; D006801:Humans; D007425:Intracellular Membranes / Q000378:metabolism; D008247:Lysosomes / Q000378:metabolism; D000076222:Mechanistic Target of Rapamycin Complex 1; D020559:Monomeric GTP-Binding Proteins / Q000378:metabolism*; D046912:Multiprotein Complexes / Q000378:metabolism*; D011485:Protein Binding; D021381:Protein Transport; D011518:Proto-Oncogene Proteins / Q000502:physiology*; D015398:Signal Transduction; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism*; D025521:Tumor Suppressor Proteins / Q000502:physiology*
chemical_list: D000596:Amino Acids; D002352:Carrier Proteins; C476078:FLCN protein, human; C516440:FNIP1 protein, human; C529782:FNIP2 protein, human; D020690:GTPase-Activating Proteins; D046912:Multiprotein Complexes; D011518:Proto-Oncogene Proteins; C430722:RRAGC protein, human; C430723:RRAGD protein, human; D025521:Tumor Suppressor Proteins; D000076222:Mechanistic Target of Rapamycin Complex 1; D058570:TOR Serine-Threonine Kinases; D020559:Monomeric GTP-Binding Proteins